Methods, devices and systems for filling body cavities

ABSTRACT

In various aspects, present disclosure is directed to methods, devices and systems whereby one or more low viscosity fluids may be introduced into a catheter and whereby the one or more low viscosity fluids may be converted into a high viscosity fluid in the catheter, which high viscosity fluid may be delivered from an exit port of the catheter.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119 to U.S.Provisional Patent Application No. 62/053,546 by Gregory Zugates et al.filed Sep. 22, 2014 and titled “Methods, Devices and Systems for FillingBody Cavities.” The entire disclosure of this reference is incorporatedherein in its entirety and for all purposes.

FIELD

Methods, devices and systems for filling body cavities are generallydescribed.

BACKGROUND

Controlling fluid, gas or material movement in the body has numerousclinical applications and benefits, including controlling hemorrhage,preventing aneurysm growth or risk of rupture, treating tumors andmanaging respiratory disorders. These treatments often requireintroduction of a material to fill or partially fill a space, potentialspace, vessel, cavity or other volume inside and/or on the surface ofthe body. However, movement of that material outside the targetedtreatment zone may have undesirable effects, cause complications, limitefficacy or lead to morbidity or mortality, among other consequences.

One clinical application in which polymers or other materials have beenused to control movement of bodily fluids is in the treatment ofaneurysms. Generally, an aneurysm is an abnormal widening or ballooningof a portion of a blood vessel due to weakness in the vessel wall. Ifleft untreated, aneurysms can grow large and rupture, causing internalbleeding which is often fatal. Two locations in which aneurysms arecommonly found are in the abdominal aorta and the brain. Other clinicalapplications in which polymers or other materials have been used tocontrol movement of bodily fluids include filling arteriovenousmalformations and blockage of feeder arteries for tumors (e.g., in thetreatment of malignant and benign tumors such as kidney lesions, liverlesions, typically hepatocellular carcinoma, and uterine fibroids).

The present disclosure is directed to methods, devices and systems forperforming these and other clinical procedures.

SUMMARY

In various aspects, present disclosure is directed to methods, devicesand systems whereby one or more low viscosity fluids may be introducedinto a catheter and whereby the one or more low viscosity fluids may beconverted into a high viscosity fluid, which high viscosity fluid may bedelivered from an exit port of the catheter.

In some aspects, the present disclosure is directed to a systemcomprising (a) a catheter comprising a first lumen having a proximal endand a distal end and an exit port proximal to a distal end of thecatheter and (b) a first low viscosity fluid. The catheter may beconfigured to receive the first low viscosity fluid at the proximal endof the first lumen, form a high viscosity fluid from the first lowviscosity fluid, and deliver the high viscosity fluid from the exit portof the catheter.

In various embodiments, the system may be configured to form the highviscosity liquid within 5 cm of the exit port of the catheter.

In various embodiments, the high viscosity liquid may be formulated tofurther cure into a solid material after delivery from the exit port ofthe catheter.

In some embodiments, the first low viscosity fluid undergoes an increasein viscosity upon exposure to light or heat, and the catheter furthercomprises a source of heat or light and is configured to expose thefirst low viscosity fluid to light or heat such that the first lowviscosity fluid is converted to the high viscosity fluid. For example,the first low viscosity fluid may comprise a polyisocyanate and an aminecatalyst and may be converted to the high viscosity fluid upon exposureto heat. As another example, the first low viscosity fluid may comprisean acrylate and a diacrylate and may be converted to the high viscosityfluid upon exposure to UV light.

In some aspects, the present disclosure is directed to a systemcomprising (a) a catheter comprising a first lumen having a proximal endand a distal end, a second lumen having a proximal end and a distal end,and an exit port proximal to a distal end of the catheter, (b) a firstlow viscosity fluid and (c) a second low viscosity liquid. The cathetermay be configured to receive the first low viscosity fluid at theproximal end of the first lumen and to receive the second low viscosityfluid at the proximal end of the second lumen. The catheter may also beconfigured to mix the first low viscosity fluid and the second lowviscosity fluid to form a high viscosity fluid and to deliver the highviscosity fluid from the exit port of the catheter.

In various embodiments, the system may be configured to form the highviscosity liquid within 5 cm of the exit port of the catheter.

In various embodiments, high viscosity liquid is formulated to furthercure into a solid material after delivery from the exit port of thecatheter (e.g., by providing a curing agent in one of the first andsecond low viscosity fluids that causes crosslinking within the highviscosity fluid after delivery from the exit port).

In some embodiments, the first low viscosity fluid may comprise amulti-functional isocyanate and the second low viscosity fluid maycomprise a multi-functional nucleophilic species.

In embodiments where a curing agent is provided, (a) the curing agentmay be one that reacts with water to form a multi-functionalnucleophilic curing species (e.g., the multi-functional nucleophiliccuring species may be a multi-functional amine, such as that provided bya multi-functional imine curing agent such as a multifunctionalketimine), (b) the curing agent may be a multi-functional nucleophiliccuring species that reacts more slowly with the diisocyanate than thedifunctional nucleophilic species, or (c) the curing agent may be amulti-functional curing species that reacts more slowly with thedifunctional nucleophilic species than the diisocyanate, among otherpossibilities.

In embodiments where a curing agent is provided and where thedifunctional nucleophilic species is a difunctional amine, (a) thediisocyanate may be over indexed and the curing agent may be adapted toreact with water in the body to cause crosslinking, (b) the diisocyanatemay be over indexed and the curing agent may be an isocyanate-reactivespecies that reacts more slowly with the diisocyanate compared to thedifunctional amine, or (c) the difunctional amine may be over indexedand the curing agent may be selected from an epoxide, alkyl chloride, anacrylate and an acrylamine, among other possibilities.

In some embodiments, the first low viscosity fluid may comprise adiisocyanate and the second low viscosity fluid may comprise adifunctional nucleophilic species selected from a difunctional amine(also referred to herein as a diamine) and a difunctional thiol (alsoreferred to herein as a dithiol), among other possibilities.

In some embodiments, the first low viscosity fluid may comprise apolyisocyanate and the second low viscosity fluid may comprise waterand, optionally, a multi-functional alcohol.

In some embodiments, the first low viscosity fluid may comprisediglycidyl ether and the second low viscosity fluid may comprise adiamine or dithiol and, optionally, a multi-functional alcohol

In some embodiments, the first low viscosity fluid may comprise divinylsulfone and the second low viscosity fluid may comprise a diamine or adithiol and, optionally, a multi-functional alcohol.

In some embodiments, the first low viscosity fluid may comprise ahydride siloxane and the second low viscosity fluid may comprise a vinylsiloxane and, optionally, a multi-functional alkene.

In some aspects, the present disclosure is directed to a method oftreating a body cavity comprising introducing a first low viscosityfluid into a proximal end of a first lumen of a catheter and deliveringa high viscosity liquid from an exit port of the catheter into the bodycavity.

In some embodiments, the method comprises exposing the low viscosityfluid to light or heat within the catheter such that the low viscosityfluid is converted to the high viscosity fluid that is delivered fromthe exit port of the catheter into the body cavity. The body cavity maybe, for example, a vascular lumen selected from an artery supplying atumor, an aneurysm and an arteriovenous malformation, among numerousother possibilities.

In some embodiments, the method further comprises introducing a secondlow viscosity fluid into a proximal end of a second lumen of thecatheter, in which case the first low viscosity fluid and the second lowviscosity fluid may be mixed to form the high viscosity fluid that isdelivered from the exit port of the catheter into the body cavity.

In some aspects, the present disclosure is directed to a cathetercomprising (a) a first lumen having a proximal end and a distal end and(b) an exit port proximal a distal end of the catheter, the catheterbeing configured receive a first low viscosity fluid at the proximal endof the first lumen, form a high viscosity liquid within 5 cm of the exitport, and deliver a high viscosity fluid from the exit port of thecatheter.

In some embodiments, the catheter further comprises a source of heat orlight and is configured to expose the first low viscosity fluid to lightor heat such that the first low viscosity fluid is converted to the highviscosity fluid within 5 cm of the exit port. For example the cathetermay comprise a source of ultraviolet light or the catheter may comprisea source of thermal energy or radiofrequency energy, among otherpossibilities.

In some embodiments, the catheter may further comprise a second lumenhaving a proximal end and a distal end, the catheter may be configuredreceive a second low viscosity fluid at the proximal end of the secondlumen, and the catheter may be configured to mix the first low viscosityfluid and the second low viscosity fluid within 5 cm of the exit portthereby forming the high viscosity fluid. The catheter may, for example,comprise a passive mixer (e.g., a T-mixer, static helical mixer,lamination mixer, etc.) and/or a dynamic mixer (e.g., rotating mixingelement, ultrasonic mixer, etc.).

In some embodiments, the catheter may comprise an elastic tip thatincreases in diameter as a result of pressure exerted by the highviscosity fluid.

In some embodiments, the catheter may comprise a self-expanding tip.

Advantages of various aspects and embodiments of the present disclosureinclude one or more of the following, among others: (a) the ability touse low profile catheters for the delivery of high viscosity materialsto a target body cavity, (b) the ability to repeatedly stop and startthe flow through such catheters, (c) the ability to deliver highviscosity materials that are retained within a target body cavity, and(d) the ability to deliver materials that conform to, or take the shapeof, and may be compliant with, a target body cavity.

These and other aspects, embodiments and advantages of the presentdisclosure will become apparent to those of ordinary skill in the artupon review of the detailed description set forth below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic illustration of a system wherein one or more lowviscosity liquid formulations undergo an increase in viscosity and theninjected into a body cavity using a catheter with an activation tip (amixing tip in the embodiment shown), in accordance with an embodiment ofthe present disclosure. FIG. 1B is a schematic illustration ofhypothetical viscosity vs. time profile for a unit volume offormulation, wherein the formulation viscosity is increased rapidly overa very short distance in the activation tip, and then continues to curein the body cavity, in accordance with an embodiment of the presentdisclosure. The time course plotted is for a unit volume of formulationthat is loaded and dispensed (where t_(a)=time to reach activation tip;t_(e)=time to reach catheter exit; t_(c)=time to reach curing; η_(L)=lowviscosity; η_(H)=high (exit or dispensed) viscosity η_(C)=curedviscosity).

FIG. 2 is a schematic illustration like that of FIG. 1A, whereinviscosity as a function of time (and thus distance) is shown for threehypothetical formulations that reach different exit viscosities, inaccordance with an embodiment of the present disclosure.

FIG. 3 is a bar graph illustrating exit viscosity as a function ofdiisocyanate-to-diamine ratio (DiNCO:DiNH₂), in accordance with anembodiment of the present disclosure.

FIG. 4A is a schematic illustration of a dual lumen mixing catheter, inaccordance with an embodiment of the present disclosure. FIG. 4B is anenlarged view of a portion of FIG. 4A, illustrating mixing of first andsecond low viscosity fluids in order to form a high viscosity fluid.

FIGS. 5A-5D are schematic illustrations of four dynamic mixing elements,in accordance with four embodiments of the present disclosure.

FIG. 6 is a schematic illustration of dual lumen catheter having dynamicmixing capability, in accordance with an embodiment of the presentdisclosure.

FIG. 7 is a schematic illustration of dual lumen catheter havingultrasonic mixing capability, in accordance with another embodiment ofthe present disclosure.

FIGS. 8A-8B are schematic illustrations of a dual lumen catheters havingan elastic, expandable catheter tip, in accordance with an embodiment ofthe present disclosure.

FIGS. 9A-9B are schematic illustrations of a dual lumen catheters havingan expandable catheter tip that is opened by retraction of a sheath, inaccordance with another embodiment of the present disclosure.

DETAILED DESCRIPTION

A more complete understanding of the present invention is available byreference to the following detailed description of numerous aspects andembodiments of the invention. The detailed description which follows isintended to illustrate but not limit the invention.

This present disclosure pertains to systems, methods and devices fordelivery of a high viscosity fluid into a body cavity. In certainembodiments, the high viscosity fluid is subsequently further cured intoa solid material after delivery within the body cavity. As used herein,a “solid” material is a material that, when placed in a container,maintains its shape and does not flow, rather than assuming the shape ofthe container or flowing.

In various embodiments, one or more low viscosity fluids are mixedwithin a catheter to form a high viscosity fluid. In variousembodiments, the catheter is a low profile catheter having a diameter of7F (2.33 mm) or less, 6F (2 mm) or less, 5F (1.67 mm) or less, 4F (1.33mm) or less, or even 3F (1 mm) or less in some embodiments.

Broadly, the high viscosity fluid will have a viscosity that is higherthan the viscosity of each of the one or more low viscosity fluids,typically at least 10 times greater than the viscosity of each or theone or more low viscosity fluids, more typically at least 1,000 timesgreater than the viscosity of each or the one or more low viscosityfluids. (Conversely, each of the one or more low viscosity fluidsbroadly will have a viscosity that is lower than the viscosity of thehigh viscosity fluid, typically at least 10 times less than theviscosity of the high viscosity fluid, more typically at least 1,000times less than the viscosity of the high viscosity fluid.) In certainbeneficial embodiments, the high viscosity fluid has a viscosity between100,000 centipoise (cP) and 1,000,000 cP or more as measured using aparallel plate rheometer with a shear rate between 1 and 10 s⁻¹. Incertain beneficial embodiments, the one or more low viscosity fluidseach may have a viscosity of 200 centipoise (cP) or less as measuredusing a parallel plate rheometer.

In various embodiments, the one or more low viscosity fluids will travelas such through most of the catheter length but will rapidly increase inviscosity near the point of exit from the catheter (e.g., within thelast 5 cm of travel through the catheter prior to exiting the catheter,within the last 2.5 cm of travel through the catheter, within the last 1cm of travel through the catheter, or even within the last 0.5 cm orless of travel through the catheter) such that a high viscosity fluidexits the catheter and is deposited in a body cavity. In certainbeneficial embodiments, the high viscosity fluid undergoes curing afterbeing deposited in the body cavity via a suitable mechanism.

Such systems are particularly advantageous for filling body cavities orvessels that are open or contain high bodily fluid flow rates, where itis important to localize the formulation proximal to the injection site(e.g., to prevent distal embolization of non-target tissue). Proceduresthat may be performed in conjunction with the systems described hereininclude the filling of aneurysms that contain blood flow frominlet/outlet blood vessels (e.g., abdominal aortic aneurysms), vascularembolization procedures (particularly those where local control isimportant), and filling of arteriovenous malformations, among many otherpossible procedures.

In an embodiment illustrated schematically in FIGS. 1A and 1B, at leastone low viscosity fluid (a pair of low viscosity liquids is shown)having a viscosity η_(L) is contained in a syringe, cartridge or otherstorage and dispensing device 15. The low viscosity fluid(s) is(are)then pushed into a catheter 10 having an activation tip (a mixing tip 17in the embodiment shown) at time t=0, beneficially, a low profilecatheter that is positioned for dispensing at the target site in asubject (i.e., a body cavity 19 to be at least partially filled). Aftera time t_(a) the fluid(s) have traveled to a point that is near the exitport 17 e of the catheter (e.g., within the 5 cm or less of the exitport 17 e), at which point an activation mechanism leads to an increasein viscosity of the fluid(s) from a low viscosity η_(L) to a highviscosity η_(H). Although the increase in fluid viscosity is caused bymixing of two low viscosity liquids in the embodiment shown, in otherembodiments a single low viscosity fluid is subjected to activationconditions (e.g., a change in temperature, exposure to light, etc.). Ata time t_(e), the resulting high viscosity fluid exits the catheter andis dispensed into the body cavity, where it can further cure andincrease in viscosity to an even higher viscosity η_(C) (at time t_(C))or cure into a solid material. An advantage of this design is theability to deploy a high viscosity fluid using a low profile catheter,which is facilitated by generating the high viscosity fluid near thepoint of exit from the catheter, which minimizes the pressure dropwithin the catheter and thus the pressure required to deploy theformulation.

Various aspects of the system, as well as their design attributes andadvantages, are summarized here:

Low Viscosity Liquid(s).

The use of low viscosity liquids permits the delivery of material withlow pressures or deployment forces. This design permits the use ofhand-actuated systems, either with or without simple mechanical leverage(e.g., springs, gears). In addition, because pressure drop isproportional to fluid viscosity and inversely proportional the fourthpower of the catheter diameter (assuming the fluid is anon-compressible, Newtonian fluid in laminar flow in a tube), lowerviscosity fluids permit the use of lower profile (diameter) cathetersfor a given pressure drop. This design feature is particularly importantfor minimally invasive devices that benefit from small catheter sizes(e.g., ≤7F).

Transition from Low to High Viscosity.

High formulation viscosities permit better control of delivery to aparticular site and retention within the target body cavity compared tolow viscosity formulations. However, for reasons stated above, a highviscosity liquid would require a large catheter diameter for delivery,which is limiting in many vascular, catheter-based procedures. Thisproblem is addressed in the present disclosure, in which a low viscositymaterial is delivered over most of the catheter length, at which pointthe fluid increases to a desirable, high viscosity liquid (i.e., onlynear the tip). This rapid, localized viscosity transition can beaccomplished by reacting lower molecular weight species in the lowviscosity liquid to form higher molecular weight species, which arecapable of further chemical reaction in the body cavity in someembodiments. For example, a rapid, localized viscosity transition may beaccomplished by polymerization of lower molecular weight prepolymer inthe low viscosity liquid to form a higher molecular weight prepolymer,which preferably is capable of further polymerization or curing in thebody cavity. Examples of mechanisms to increase the viscosity of aprepolymer-containing liquid include mixing two reactive liquid phases,heating a thermally unstable liquid prepolymer formulation, or applyingultraviolet (UV) light to photopolymerize a liquid formulation, amongothers.

Formulation Curing.

The high viscosity state of the formulation will enable it be retainedwithin a body cavity and conform to an irregular shape (e.g., conformingto the shape of the body cavity). Depending on the application, theformulation may continue to flow over time and spread outside of thetarget region/cavity. In these cases, it is advantageous for thematerial to cure or crosslink into a solid, non-flowable mass so that itremains isolated within the target site. Furthermore, this transitionwill enable the material to provide mechanical support to the cavity andsurrounding tissues.

As previously indicated, one mechanism for activating a first lowviscosity fluid is to mix the first low viscosity fluid with a secondlow viscosity fluid which reacts very quickly (near instantaneously)with the first low viscosity fluid to create a high viscosity liquid.For example, a first low molecular weight, low viscosity fluid may bemixed and reacted with a second low viscosity fluid to create a highmolecular weight, high viscosity liquid.

In various embodiments, the first low viscosity fluid comprises amulti-functional (i.e., having a functionality of 2 or more) isocyanate,typically, a diisocyanate, and the second low viscosity fluid comprisesa multi-functional nucleophilic species, typically a difunctionalnucleophilic species. Examples of nucleophilic species which react withisocyanates include amines (forming ureas or polyureas) and thiols(forming thiocarbamates or polythiocarbamates), alcohols (formingurethanes or polyurethanes) and water (forming ureas or polyureas aswell as carbon dioxide).

One example of a reaction of this type is shown in Formula [I] below:

More particularly, upon being mixed in an activation tip of a catheter(discussed in more detail below), a diisocyanate (e.g., a low molecularweight isocyanate-terminated polymer) reacts with a diamine (e.g., a lowmolecular weight amine-terminated polymer) to form a linearisocyanate-terminated polyurea with high molecular weight and highviscosity. In is embodiment, the diisocyanate is over-indexed (i.e., inexcess) relative to the diamine, such that a linearisocyanate-terminated polyurea is formed (and isocyanate remainsavailable for further reaction). In other embodiments, the diamine maybe over-indexed relative to the diisocyanate such that a linearamine-terminated polyurea is formed (and amine remains available forfurther reaction).

In one particular embodiment, a linear silicone polyurea, for example, apolydimethylsiloxane (PDMS) based urea, is formed by admixing twolow-viscosity di-functional silicones, for example, by mixing a lowviscosity isocyanate-terminated silicone with a low viscosityamine-terminated silicone. One example of a low viscosityisocyanate-terminated silicone is PDMS diisocyanate, for example asshown in formula [II]:

In the formula, x is an integer beneficially ranging, for example, from1 to 10, among other possible values, more preferably from 1 to 5, evenmore preferably 3, and n is an integer ranging, for example, from 5 to300, among other possible values, more preferably from 5 to 80. Oneexample of a low viscosity amine-terminated silicone is PDMS diamine,for example as shown in Formula [III] below,

where n is an integer independently ranging, for example, from 5 to 300,among other possible values, more preferably from 5 to 80.

Importantly, the high exiting viscosity (η_(H)) can be controlled overseveral orders of magnitude by adjusting the ratio between thediisocyanate and the diamine (DiNCO:DiNH₂). In this regard, FIG. 3graphically illustrates exit viscosity as a function of the DiNCO:DiNH₂ratio. The neat condition is pure diisocyanate, prepared by reactingGelest carbinol DMS-C21 (a hydroxypropyl-terminatedpolydimethylsiloxane, 500-1000 mol. wt., available from Gelest, Inc.,Morrisville, Pa., USA) with excess isophorone diisocyanate (IPDI). Thediamine used is Gelest DMS-A21, an aminopropyl-terminated PDMS, mol. wt.5000-7000, available from Gelest, Inc. As seen from FIG. 3, viscosityincreases ˜1300 times when the DiNCO:DiNH₂ ratio is varied from 10:1 to1:1.

Furthermore, where over-indexing of either the diisocyanate or diamineis employed, the high molecular weight prepolymer formed is capable offurther reaction at the chain termini. For example, over-indexing theisocyanate leads to a prepolymer than can further react with water inthe body cavity (leading to further increases in molecular weight andviscosity), or with an added agent that leads to crosslinking

Diisocyanate polymers can be prepared by several methods, including forexample, phosgenation of polyamines (e.g., PDMS diamine), and Curtiusrearrangement of acyl azides (prepared from diacids and/or diacidchlorides using trimethylsilyl azide). Diisocyanate polymers can beprepared by reaction of a difunctionalized polymer such as a diolpolymer, diamine polymer, or diacid polymer, among others, withdiisocyanate, in which case quasi-prepolymers may be formed (e.g., whereexcess or residual free isocyanate monomer is present) orstrict-prepolymers may be formed (e.g., when just enough polyisocyanateis added to react with all functional sites available).

In some applications, the high viscosity fluid that exits the cathetermay be the desired end product. However, in many cases, it is preferredto transition the material to a solid to provide mechanical support andlong-term localization of the material (i.e., prevent flow or migrationof the material out of the target area). A particularly beneficialmechanism for inducing fluid-to-solid transition is to add a curingagent (i.e., a crosslinking agent) to the formulation that actsindependently, or substantially independently, of the reaction betweenthe first and second low viscosity fluids. In this manner, the processesleading to viscosity increases and the processes leading to curing(i.e., crosslinking) can be independently controlled and designed.

In some embodiments, a curing agent is selected which reacts with waterin the body to cause crosslinking For example, in embodiments where alow viscosity fluid comprising a difunctional nucleophilic species ismixed with a low viscosity fluid comprising a diisocyanate, and whereexcess diisocyanate is employed, the curing agent may be a species whichis substantially non-reactive with isocyanate before exposure to water,but which becomes reactive upon being exposed to water. In one specificexample where a low viscosity fluid comprising a diamine is mixed with alow viscosity fluid comprising a diisocyanate, a multi-functional (i.e.,having a functionality 2 or more) ketimine may be selected as a curingagent, for which exposure to water or moisture results in hydrolysis ofthe imine functionalities to form amines. The amines can then react withand cure the isocyanate-terminated high viscosity polyurea that isformed by prior reaction of the diamine and diisocyanate. In aparticular embodiment, the ketimine is a low viscosity polymer, whichcan be made, for example, by a dehydration reaction between amulti-functional PDMS amine and methyl ethyl ketone (MEK) to yield aPDMS ketamine as shown in Formula [IV] below:

In formula [IV], m is an integer ranging, for example, from 5 to 80,among other possible values, and n is an integer ranging, for example,from 2 to 10, among other possible values.

In some embodiments, a curing agent is selected which reacts more slowlythan the primary reacting species. For example, in embodiments where alow viscosity fluid comprising a diamine is mixed with a low viscosityfluid comprising a diisocyanate, and where excess diisocyanate isemployed, the curing agent may be a species that reacts more slowly withthe isocyanate than amine. One specific example of such a species is amulti-functional alcohol (alcohols react approximately 1,000-fold slowerthan primary amines). A specific example of a multi-functional alcoholpolymer is a low viscosity PDMS carbinol as shown in Formula [V] below:

where m is an integer ranging, for example, from 5 to 80, among otherpossible values, n is an integer ranging, for example, from 2 to 10,among other possible values, and p is an integer ranging, for example,from 0 to 30 among other possible values.

As another example, in embodiments where a low viscosity fluidcomprising a diamine is mixed with a low viscosity fluid comprising adiisocyanate, and where excess diamine is employed, the curing agent bea species that that reacts more slowly with the diamine thandiisocyanate. Examples of such species include epoxides (e.g.,trimethylolpropane triglycidyl ether, etc.), alkyl chlorides (e.g.,dichlorohexane, etc.), acrylates (e.g., trimethylolpropane ethoxylatetriacrylate, etc.), and acrylamides (e.g.,N,N′-methylenebis(acrylamide), etc.).

Where a curing agent is selected which reacts more slowly than theprimary reacting species, the slower crosslinking reaction enables thehigh viscosity prepolymer to mold or conform to the body cavity prior tosolidification. By adjusting the amount of catalyst and the type/amountof curing agent, the curing rate may be independently tuned to occurover a clinically relevant time period, while allowing sufficient timefor multiple stop/starts during the injection procedure (so that thecatheter does not become plugged with cured material).

Additional examples of reactions which may be employed to produce highviscosity fluids from low viscosity fluids will now be described.

For example, in some embodiments, a low viscosity fluid comprising amulti-functional isocyanate polymer (i.e., having a functionality of 2,3 or more) may be reacted with a low viscosity fluid comprising water(or bodily fluid) to form a fluid of increased viscosity that comprisesa polyurea. Where the isocyanate is over-indexed relative to the water,a multi-functional alcohol may be employed as a curing agent.

As another example, in some embodiments, a low viscosity fluidcomprising divinyl sulfone may be reacted with a low viscosity fluidcomprising a diamine (e.g., PDMS diamine) to form a fluid of increasedviscosity. Where the divinyl sulfone is over-indexed relative to thediamine, a multi-functional alcohol like that described above, amongothers, may be employed as a curing agent.

Thiols may be substituted for amines in various embodiments describedherein.

As yet another example, in some embodiments, a low viscosity fluidcomprising a hydride siloxane, for example, a polysiloxane containingreactive hydrogen-to-silicon bonds such as a hydrogen-terminateddimethyl polysiloxane may be reacted with a low viscosity fluidcomprising a vinyl siloxane, for example, a vinyl terminatedpolysiloxane to form a fluid of increased viscosity. Where the hydridesiloxane is over-indexed relative to the vinyl siloxane, amulti-functional alkene (e.g., triallyl isocyanurate, among others) maybe employed as a curing agent.

As previously noted, in various embodiments of the disclosure, fluidviscosity is increased by subjecting a single low viscosity fluid tosuitable activation conditions such as, for example, a change intemperature or exposure to light, among other possibilities.

In some embodiments, a low viscosity fluid is delivered along the lengthof a catheter and converted to a high viscosity liquid at the cathetertip by the application of heat. Further reaction or crosslinkingpreferably occurs in the body cavity to solidify the material andprevent continued flow.

One example of a heat activated formulation is one that comprises amulti-functional isocyanate mixed with an amine catalyst. In oneembodiment, the multi-functional isocyanate is a silicone triisocyanate,specifically, an IPDI-terminated PDMS, prepared by reacting Gelestcarbinol CMS-222 (a(hydroxypropyleneoxypropyl)methylsiloxane-dimethylsiloxane copolymer,also known as hydroxypropylene oxide modified polydimethylsiloxane,5000-7000 mol. wt., available from Gelest, Inc.) with excess IPDI, andthe amine catalyst is 1,8-diazabicycloundec-7-ene (DBU). This specificformulation will cure within several minutes at room temperature to forma crosslinked polyisocyanurate gel. Depending on the heat applied (i.e.,the temperature increase applied to the formulation), the cure time maybe reduced to several seconds or less. Because the material containsisocyanate groups, only partial curing may need to occur within thecatheter tip (to increase viscosity), because further reaction thatleads to full curing can be allowed to occur within the body cavity.

Other suitable formulations include those employing other combinationsof species that react/cure within several minutes at room temperature,for example, an epoxy-amine system, among other possibilities. As above,depending on the heat applied to the formulation, the cure time may bereduced to several seconds or less.

In other embodiments, a low viscosity fluid is delivered along thelength of a catheter and converted to a high viscosity liquid byirradiating the low viscosity fluid with visible or ultraviolet (UV)light at the catheter tip. Further reaction or crosslinking may becaused to occur in the body cavity to solidify the material and preventcontinued flow, for example, using water, pH or temperature to inducecuring.

One example of a light-activated formulation is one that comprises anacrylate (e.g., hexyl acrylate, etc.), a diacrylate (e.g., PDMSdiacrylate, poly(ethylene glycol) diacrylate, 1,4-butanediol diacrylate,etc.), and a photoinitiator (e.g., 2,4,6-trimethylbenzoyldiphenylphosphine oxide, etc.). The polymer molecular weight betweencrosslinks and mechanical properties can be controlled by controllingthe molecular weight of the diacrylate and the relative concentrationsof each component. Furthermore, cure may be achieved by copolymerizingacrylates with polymers or monomers containing moisture reactivefunctionality (functionality greater than 2), such as those havingisocyanate or ethoxysilane functionality, among other possibilities.

In various embodiments, the high viscosity reached at the catheter exitcan be adjusted, depending on the application. For example, in caseswhere exit viscosity is on the lower side (e.g., to reduce the pressurerequired for delivery), it may be desirable to have a fast cure rate inorder to enhance retention the formulation at the target site.

In this regard, FIG. 2 shows viscosity as a function of time for threehypothetical formulations, each reaching differing exit viscosities. Toprovide adequate retention of the formulation at the target site,particularly for formulations that have lower exit viscosities (η_(H)),it may be desirable to select faster cure rates (Δη/Δt), which likewiseresults in shorter cure times (t_(C)).

Suitable catheters for the delivery of one or more low viscosityfluid(s) that react to high viscosities within the catheter are alsodescribed herein. Such catheters preferably deliver high viscositymaterial by application of a reasonable amount of pressure, preferablyby the means of a hand powered device.

In various embodiments, delivery is enhanced by activating theformulation as close to the catheter tip as possible, for example,within 5 cm of the exit port of the catheter, within 2.5 cm of the exitport of the catheter, within 1 cm of the exit port of the catheter, oreven within 0.5 cm or less of the exit port of the catheter, in someembodiment. For systems in which two low viscosity fluids are combined,the catheter is provided with means of mixing the fluids within a veryshort time and length scale.

Depending on the embodiment, the mixing mechanism employed in thecatheter may be passive or active. Passive mixing relies only on thepressure from the fluid flow to create shear and increase the area ofinterfacial contact in conjunction with physical impediments (i.e.,mixing elements), whereas in active mixing, additional energy is inputinto the system.

Passive mixing is advantageous in that the system is less complex.Examples of passive mixers that may be employed in catheter systemsdescribed herein include static helical mixers, lamination mixers, andT-mixers.

An exemplary T-mixer catheter system, which has been shown inmicrofluidics research to provide mixing at low Reynolds numbers over asmall length and time scale is schematically illustrated in FIGS. 4A and4B, which shows dual lumen catheter 40, which has a first catheter lumen42 carrying a first low viscosity fluid A and a second catheter lumen 44carrying a second low viscosity fluid B. In this design, the two lumens42, 44 in the dual lumen catheter 40 end in distal segments 42 s, 44 sthat direct fluid a, b out of holes 42 h, 44 h in the distal segments 42s, 44 s in a direction that is perpendicular to the final flow directionof the mixed material C for the exit port 40 e of the catheter 40. Thestreams a, b emerging from the holes 42 h, 44 h are aligned and suchthat the streams collide with one another. The intersection of the twoflows a, b causes rapid mixing in a mixing volume confined by the sheath46. The holes 42 h, 44 h preferably have a width that is small enough tocreate sufficient fluid velocity to cause efficient mixing. In certainembodiments, the holes 42 h, 44 h may range, for example, from 0.05mm-0.5 mm in diameter, preferably ranging from 0.05 mm-0.25 mm. Sinceeach hole 42 h, 44 h is formed in a side wall of each distal segment 42s, 44 s, the distance traveled by each fluid is the thickness of theside wall, minimizing the increase in system pressure associated withthe distal segments 42 s, 44 s. The exit velocity of the two fluids a, band the distance from the catheter exit port 40 e may be adjusted basedon the amount of mixing desired.

Active mixing, although somewhat more complex, is advantageous in termsof mixing efficiency and required input pressure over passive mixing.Since the energy to mix the two fluids is supplied externally, thepressure required for fluid flow is not increased. An example of anactive mixer is a rotating hoop that creates shear at the walls of thecatheter, enhancing mixing of the two fluids.

A system of this type is schematically illustrated in FIG. 6, whichshows a dual lumen catheter 60, which has a first catheter lumen 62carrying a first low viscosity fluid A and a second catheter lumen 64carrying a second low viscosity fluid B. The streams of fluid a, bemerging from the lumens 62, 64 are mixed in a volume confined by sheath66 using a rotating hoop 65. Rotation of the hoop 65 is driven by anelectrical motor 61 via a driveshaft 63. The outside diameter of thehoop 65 preferably matches as closely as possible the inside diameter ofthe catheter sheath 66 to minimize stagnant flow locations that maydevelop against the wall. In some embodiments, the driveshaft ispreferably made up of a braided torque wire that has close to 1:1 torqueto eliminate potential binding.

For viscous materials, open mixing element such as a hoop, or an opendesign analogous to those used for mixing cake batter, or low Reynoldsnumber batch mixing (an anchor or helical ribbon) are much moreefficient than traditional impellers. A single hoop allows for theremoval and insertion of the mixing element in a dual lumen catheterbecause it is substantially planar. This is ideal for a system thatrequires guidewire access. Once the catheter is placed over theguidewire and the guidewire removed, the mixer may be inserted andplaced through the same lumen if sized appropriately. In addition to asimple hoop design such as that shown in FIG. 5A, to improve the mixinglength of the device (and minimize stagnant flows spots), the hoop maybe elongated as shown in FIG. 5B. The hoop may also be rectangular inshape, if desired. If additional shear is desired to mix the components,additional structures can be added as shown in FIGS. 5D and 5E.

In alternative embodiments, the need for a driveshaft may be avoided byusing a magnetically driven impeller. The impeller may contain a magnetand be driven by an electromagnetic coil placed adjacent the magnet nearthe tip of the catheter.

In further alternative embodiments, the two fluids may be mixed at thetip of the catheter using an acoustic stirring effect produced byultrasonic waves. A system of this type is schematically illustrated inFIG. 7, which shows a dual lumen catheter 70, which has a first catheterlumen 72 carrying a first low viscosity fluid A and a second catheterlumen 74 carrying a second low viscosity fluid B. An ultrasonicfrequency generator 71 is connected to a wire 73 that travels the lengthof the catheter 70 and extends into the mixing chamber defined by thesheath 76 where the two fluids come together. The ultrasonic wavesemitted from the wire 73 cause the two components to become well mixed.In the particular embodiment shown, as in FIGS. 4A-4B discussed above,each of the two lumens 72, 74 in the dual lumen catheter 70 ends in asegment that forces the material out perpendicular to the final flowdirection. The two streams collide with each other and the ultrasonicmixing wire 73 which emits an ultrasonic frequency causing the twocomponents A, B to be acoustically mixed as well.

Delivery can be enhanced by increasing the diameter of the catheter tipto counteract the increase in pressure associated with the increasingviscosity. In some embodiments, >50% of the pressure drop in the systemoccurs at the active tip (e.g., within the last 1 cm) where the materialviscosity increases. For circular conduits, pressure drop is inverselyproportional to the fourth power of the radius (i.e., α r⁻⁴). Therefore,a slight increase in width at the catheter tip can substantially reducethe overall pressure of the system.

In order to allow the delivery of the material in a minimally invasiveway, the catheter may beneficially have a smooth and constant outerdiameter (OD) upon insertion. To reduce system pressure, however, it isdesirable in some embodiments that the catheter tip be configured to beenlarged post-insertion and at the target site. This can be achieved invarious ways including the use of an elastic membrane or aself-expanding tip that is housed in a sheath, among other options. Incertain embodiments, the mixing chamber of the catheter is located justupstream of the expandable tip to allow for adequate mixing and shearingat the catheter wall. Two of these concepts are schematically illustratein FIGS. 8A-8B and 9A-9B.

Turning to FIG. 8A, a system is schematically shown which includes adual lumen catheter 80, which has a first catheter lumen 82 carrying afirst low viscosity fluid A and a second catheter lumen 84 carrying asecond low viscosity fluid B. The catheter includes a mixing chamber 87and an elastic catheter tip 89 formed of an elastic material such assilicone (e.g., PDMS), Latex, EPDM (ethylene propylene diene monomer)rubber, and other rubbers, among other possibilities. The elasticcatheter tip 89 is attached just distal to the mixing chamber 87 and hasa resting (unstressed) outer diameter approximately the same as theremainder of the dual lumen catheter 80. As discussed above, when thefirst and second low viscosity fluids A, B mix they form a highlyviscous material that will dramatically increase the system pressure.This increase in pressure will stretch the elastic material of thecatheter tip 89 as shown in FIG. 8B. As the material of the catheter tip89 stretches, the inner diameter of the catheter tip 89 increases,resulting in a reduction of pressure. The elasticity of the materialforming the catheter tip 89 can be tailored to allow a specific androbust amount of stretch based on the pressure experienced. In certainembodiments, the elastic tip ranges from 0.1-5 cm in length L, andpreferably ranges from 0.1-1 cm in length L.

Another system in which the catheter tip is self-expanding isschematically illustrated in FIG. 9A, which shows a dual lumen catheter90, which has a first catheter lumen 92 carrying a first low viscosityfluid A and a second catheter lumen 94 carrying a second low viscosityfluid B. The catheter includes a mixing chamber 97 and a self-expandingcatheter tip 99. The self-expanding catheter tip 99 is flared and housedin a retractable sheath 98. The tip can 99 may be formed of aself-expanding material that self-expands (e.g., due to an elastic shapememory effect), or the tip 99 may comprise a structure similar to acovered self-expanding stent. When the sheath is retracted as shown inFIG. 9B, the tip 99 self-expands into a flared configuration. After theprocedure is complete, the self-expanding tip 99 can then be pulled backinto the sheath, compressing the tip 99 to a reduced diameter forremoval. In certain embodiments, the elastic tip ranges from 0.1-5 cm inlength L, and preferably ranges from 0.1-1 cm in length L. In analternative embodiment, the tip may comprise a pre-formed thin plasticflare that is folded and opens fully when material is injected.

For heat-activated systems, in some embodiments, a delivery catheter maybe provided which is configured to apply heat only at the tip of thecatheter, preferably, within 5 cm of the exit port of the catheter. Inone embodiment, a heat source comprises a heated wire that runs throughthe catheter. The wire is uninsulated within 5 cm of the exit port, butis insulated elsewhere, thus transferring heat to the formulation at thedistal tip of the catheter. The wire can be formed into any shape orpattern necessary to provide suitable heat transfer. For example, thewire can be coiled around the tip, either internal or external orembedded within the wall of the lumen, or the wire may be providedwithin the catheter lumen, for example, in the form of mesh or grid thatthe formulation is passed through (thereby providing enhanced heattransfer).

In another embodiment of the delivery catheter, radiofrequency (RF)energy may be used as the heat source. For example, an RF source may beemployed that transmits the desired frequency along a cable and emitsthe energy only within 5 cm of the exit port, heating the formulationand initiating reaction of the formulation.

For light-activated systems, the delivery catheter can be designed toprovide UV or visible light within 5 cm of the exit port. In oneembodiment, light can be provided using power supply connected to alight emitting diode (LED). In some embodiments, the LED is positionedto directly provide illumination within 5 cm of the exit port. In otherembodiments, the LED is further connected to a thin fiber optic cable.The fiber optic cable runs down the center of the catheter andterminates preferably within 5 cm of the exit port. Light at a specifiedwavelength, supplied by the (LED), will either exit the LED directly orexit the fiber optic cable and initiate reaction of the formulation. Thewavelength and intensity of the light, as well as the numerical apertureof the fiber optic cable, may all be selected to provide the idealcuring profile of the formulation

In various embodiments described herein, heat may be applied along thelength of the catheter to maintain a low formulation viscosity, but thenrapidly cooled within the catheter tip to increase the exitingviscosity.

In various embodiments described herein, for a two part system, a firstlow viscosity fluid A and a second low viscosity fluid B are heatedseparately in the catheter, in order to lower the viscosity of fluids Aand B for ease of delivery. Once fluid A is mixed with fluid B near theexit port, the mixture may be heated further, if desired, to speed upthe reaction of the two parts and increase the exiting viscosity.

Although various embodiments are specifically illustrated and describedherein, it will be appreciated that modifications and variations of thepresent disclosure are covered by the above teachings and are within thepurview of the appended claims without departing from the spirit andintended scope of the invention.

The invention claimed is:
 1. A system comprising (a) a catheter having proximal and distal ends and comprising first and second lumens, at least one of the first and second lumens terminating in an exit port proximal to the distal end of the catheter, (b) a mixing element located in the catheter at a portion of the distal end of the catheter proximal to the exit port and fluidly communicating with the first and second lumens, and (c) first and second low viscosity fluids, wherein the catheter is configured to receive the first low viscosity fluid at the proximal end of the first lumen and to receive the second low viscosity fluid at the proximal end of the second lumen and to mix the first and second low viscosity fluids between the exit port and portion of the of the catheter where the mixer and first and second lumens are in fluid communication, thereby forming and expelling a high viscosity fluid from the catheter, said high viscosity fluid having a viscosity from 100,000 to 1,000,000 cP as measured using a parallel plate rheometer with a shear rate between 1 and 10 s⁻¹.
 2. The system of claim 1, wherein the catheter is configured to mix the first low viscosity fluid and the second low viscosity fluid within 5 cm of the exit port.
 3. The system of claim 1, wherein the high viscosity liquid is configured to further cure into a solid material after delivery from the exit port.
 4. The system of claim 1, wherein the first low viscosity fluid comprises a multi-functional isocyanate and the second low viscosity fluid comprises a multi-functional nucleophilic species.
 5. The system of claim 1, wherein the first low viscosity fluid comprises a diisocyanate and the second low viscosity fluid comprises a difunctional nucleophilic species selected from a difunctional amine and a difunctional thiol.
 6. The system of claim 1, wherein one of the first and second low viscosity fluids comprises a curing agent that causes crosslinking within the high viscosity fluid after delivery from the exit port.
 7. The system of claim 1, wherein the first low viscosity fluid comprises a polyisocyanate and the second low viscosity fluid comprises water and a multi-functional alcohol.
 8. The system of claim 1, wherein the first low viscosity fluid comprises diglycidyl ether and the second low viscosity fluid comprises a diamine or dithiol.
 9. The system of claim 1, wherein the first low viscosity fluid comprises divinyl sulfone and the second low viscosity fluid comprises a diamine or a dithiol.
 10. The system of claim 1, wherein the first low viscosity fluid comprises a hydride siloxane and the second low viscosity fluid comprises a vinyl siloxane and, optionally, a multi-functional alkene.
 11. A method of treating a patient comprising the steps of: inserting into the body of the patient, a distal end of a catheter having first and second lumens, wherein the catheter is configured to receive a first low viscosity fluid at a proximal end of the first lumen and to receive a second low viscosity fluid at a proximal end of the second lumen, at least one of said lumens terminating in an exit port proximal to the distal end of the catheter, and including a mixing element located in the catheter at a portion of the distal end of the catheter proximal to the exit port, said mixing element fluidly communicating with the first and second lumens; and flowing first and second low viscosity fluids through the first and second lumens of the catheter, respectively, and over the mixing element, thereby forming and expelling a high viscosity fluid into the body of the patient, said high viscosity fluid having a viscosity from 100,000 to 1,000,000 cP as measured using a parallel plate rheometer with a shear rate between 1 and 10 s⁻¹.
 12. The method of claim 11, wherein the high viscosity liquid is configured to further cure into a solid material after delivery from the exit port of the catheter.
 13. The method of claim 11, wherein the first low viscosity fluid comprises a multi-functional isocyanate and the second low viscosity fluid comprises a multi-functional nucleophilic species.
 14. The method of claim 11, wherein one of the first and second low viscosity fluids comprises a curing agent that facilitates or causes a crosslinking reaction within the high viscosity fluid.
 15. The method of claim 11, wherein the first low viscosity fluid comprises a polyisocyanate and the second low viscosity fluid comprises water and a multi-functional alcohol.
 16. The method of claim 11, wherein the first low viscosity fluid comprises diglycidyl ether and the second low viscosity fluid comprises a diamine or dithiol.
 17. The method of claim 11, wherein the first low viscosity fluid comprises divinyl sulfone and the second low viscosity fluid comprises a diamine or a dithiol.
 18. The method of claim 11, wherein the first low viscosity fluid comprises a hydride siloxane and the second low viscosity fluid comprises a vinyl siloxane and, optionally, a multi-functional alkene.
 19. A method of treating a patient comprising the steps of: inserting into the body of the patient, a distal end of a catheter having first and second lumens, wherein the catheter is configured to receive a first low viscosity fluid at a proximal end of the first lumen and to receive a second low viscosity fluid at a proximal end of the second lumen, at least one of said lumens terminating at an exit port proximal to the distal end of the catheter and including a mixing element located in the catheter at a portion of the distal end of the catheter proximal to the exit port, said mixing element fluidly communicating with the first and second lumens; and flowing first and second low viscosity fluids through the first and second lumens of the catheter, respectively, and over the mixing element, thereby forming and expelling a high-viscosity fluid into the body of the patient, wherein the first low viscosity fluid includes a polyisocyanate and the second low viscosity fluid comprises water and a multi-functional alcohol and wherein the high viscosity fluid has a viscosity of from 100,000 to 1,000,000 cP as measured using a parallel plate rheometer with a shear rate between 1 and 10 s⁻¹.
 20. The method of claim 19, wherein the second low viscosity fluid includes at least one of a diamine, a dithiol, a vinyl siloxane and a multi-functional alkene. 